Group B streptococcus vaccines: one step further.

In The Lancet Infectious Diseases, Judith Absalon and colleagues report on a phase 1/2 clinical trial evaluating the safety, tolerability, and immunogenicity of a vaccine composed of capsular polysaccharide conjugated to cross-reactive material 197 (CRM197) and directed against six capsular polysaccharide serotypes of group B streptococcus (GBS). These serotypes (Ia, Ib, II, III, IV, and V) account for the vast majority of isolates causing invasive GBS disease worldwide—in neonates as well as in adults.2, 3, 4 The authors report that three different doses of this hexavalent vaccine formulated with or without aluminium phosphate as its adjuvant were safe and well tolerated in healthy, non-pregnant, adult volunteers. The vaccine elicited a robust immune response for at least 6 months.

It is a good point in time to report some success with a GBS vaccine. In the era of COVID-19 and the worldwide anticipation of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine, it might appear as if vaccine development works as in the proverb that states that where there's a will, there's a way. For GBS vaccines, progress has been very difficult. In the 1980s, pioneers Carol Baker and Dennis Kasper started to investigate polysaccharide-based GBS vaccines. In 1988, they showed that maternal immunisation against GBS is feasible, but immunogenicity of GBS polysaccharide-based vaccines was weak. In 1996, a phase 1 trial with conjugate vaccines prepared with GBS type-specific capsular polysaccharide coupled to protein antigens induced stronger immune responses than capsular polysaccharide alone. Although more than 20 years have elapsed since then, unfortunately no GBS vaccine has been licensed. In the meantime, pneumococcal, meningococcal, and Haemophilus influenzae type b conjugate vaccines have all been licensed. Several phase 1 and 2 studies of GBS vaccines have been done, including that by Absalon and colleagues. The results often are very encouraging—as in this study—but the next steps that are urgently needed, including studies in pregnant women, analysing the passive antibody transfer to the neonate, and subsequently assessing protection against disease, are often not taken.

There is an urgent need for a global strategy to protect the most vulnerable population—neonates and young infants up to age 3 months—against this sometimes devastating disease, which can cause neonatal GBS sepsis and meningitis, and which is an unresolved challenge, especially in low-income countries. GBS is estimated to cause more than 300 000 cases of neonatal disease annually, resulting in roughly 90 000 infant deaths worldwide. GBS is also associated with maternal sepsis, stillbirths and preterm births, and severe neurological impairment among patients who survive neonatal meningitis. Intrapartum antibiotic prophylaxis has substantially reduced the incidence of early onset GBS disease in high-income countries that have implemented this strategy; however, this strategy is not feasible in many low-income and middle-income countries. Moreover, intrapartum antibiotic prophylaxis will not protect against late-onset GBS disease, which in most cases is transmitted postnatally. By contrast, a vaccine given to pregnant women to stimulate passive transplacental transfer of protective antibodies has the potential to reduce maternal disease, adverse pregnancy outcomes, and newborn early onset and late-onset disease. Maternal IgG is actively transported across the placenta, providing passive immunity. Of course, the risks and benefits of maternal vaccination must always be carefully weighed and analysed, and protection of the mother and the fetus must be prioritised.

The next step would then be doing efficacy studies, which for a GBS vaccine candidate is a difficult task. It would require large numbers of immunised mothers because of the low incidence of neonatal GBS disease. It has therefore been proposed that alternative options to vaccine licensure should be explored. Recent studies suggest that maternal capsular antibody thresholds could be used as immunological correlates of protection. Thus, a regulatory approved correlate of protection and safety evaluation in mothers, fetuses, and infants are needed.8, 9 After the vaccine is licensed, phase 4 studies would then have to follow to evaluate vaccine effectiveness.

Beyond conjugate vaccines, which have some limitations, surface proteins, as candidate vaccines with or without being coupled to the capsular polysaccharide, might broaden protection against invasive GBS disease. However, the immunogenic potential of pilus island and other GBS surface proteins, which has been shown in animal-model studies, could not be confirmed by association analysis of maternal antibody concentration and invasive GBS disease in infants. Therefore, the study by Absalon and colleagues is particularly important and encouraging. The hexavalent conjugate vaccine covers the majority of invasive serotypes worldwide. Serotype replacement should be kept in mind as a potential problem, but should not hamper further steps. In these days of the SARS-CoV-2 pandemic, when awareness of the paramount importance of vaccine development is as high as ever, the time has come to initiate the required studies designed to prove immunogenicity of a hexavalent vaccine in pregnant women, diaplacental transfer of antibodies, and protection of neonates from disease, disability, or death.